title: Use of DAF-displaying adenovirus vectors reduces induction of transgene- and vector-specific adaptive immune responses in mice.
abstract: Adenovirus (Ad)-based vectors are attractive candidates for a variety of gene-transfer applications. In this study, we found that decay-accelerating factor (DAF)-displaying Ads induce significantly decreased cellular immune responses to transgenes expressed from the vectors in both Ad5-naive and Ad5-immune mice. Specifically, we found a diminished ability of splenocytes to secrete interferon-γ after recall exposure to multiple peptides derived from antigens expressed by DAF-displaying Ads. We also confirmed that DAF-displaying Ads induce decreased numbers of antigen-specific, CD8(+) effector memory and central memory CD8(+) T cells, thereby uncovering a unique role of complement in modulating the induction of robust memory T-cell responses. We also confirmed that DAF-displaying Ads generate significantly reduced titers of Ad capsid-specific neutralizing antibodies after gene transfer in vivo. In conclusion, DAF-displaying Ad5-based vectors exhibit decreased induction of complement-dependent, innate immune responses, resulting in both an improved safety profile and a decreased propensity to induce humoral and cellular adaptive immune responses to Ad capsid proteins and Ad vector-expressed transgene products. This attractive combination of features will be beneficial in a variety of clinically relevant gene-transfer applications.
authors.affiliation: Department of Microbiology and Molecular Genetics, College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Sergey S
authors.initials: SS
authors.lastname: Seregin
authors.forename: Yasser A
authors.initials: YA
authors.lastname: Aldhamen
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Appledorn
authors.forename: Jennifer
authors.initials: J
authors.lastname: Zehnder
authors.forename: Tyler
authors.initials: T
authors.lastname: Voss
authors.forename: Sarah
authors.initials: S
authors.lastname: Godbehere
authors.forename: Andrea
authors.initials: A
authors.lastname: Amalfitano
mesh_terms: D056704:Adaptive Immunity; D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology*; D000818:Animals; D018958:CD55 Antigens / Q000235:genetics*; D000939:Epitopes / Q000276:immunology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D014161:Transduction, Genetic; D019076:Transgenes
chemical_list: D018958:CD55 Antigens; D000939:Epitopes